EP3655441A1 - Asprv1 als neutrophilenspezifischer marker und therapeutisches target für entzündliche erkrankungen - Google Patents
Asprv1 als neutrophilenspezifischer marker und therapeutisches target für entzündliche erkrankungenInfo
- Publication number
- EP3655441A1 EP3655441A1 EP18836128.1A EP18836128A EP3655441A1 EP 3655441 A1 EP3655441 A1 EP 3655441A1 EP 18836128 A EP18836128 A EP 18836128A EP 3655441 A1 EP3655441 A1 EP 3655441A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- asprvl
- neutrophils
- antibody
- fragment
- antigen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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- G01N2333/96427—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general
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Definitions
- ASPRVl is required for the chronic phase of EAE induced with a B cell-dependent myelin antigen (bMOG), but not for initial neutrophil recruitment or T cell priming, a, Kaplan-Meier plot of EAE incidence in wild-type (ASPRV1 +/+ ) and ASPRVl-deficient mice (ASPRVl -7- ) after immunization with either MOG35-55 or bMOG. Shaded area represents the 95% pointwise confidence interval. For sample size and statistical testing, see incidence in c. b, Severity of EAE over time by group versus time from appearance of first symptoms. P-value shown on graph was calculated by two-way ANOVA with repeated measures using rank-transformed scores.
- binding fragments encompassed within the term "antigen-binding fragment" of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHI domains; (ii) a F(ab') 2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the V H and CHI domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., (1989) Nature 341:544-546), which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR), e.g., VH CDR3.
- CDR complementarity determining region
- a “detectable moiety” is a moiety detectable by spectroscopic, photochemical, biochemical, immunochemical, enzymatic, chemical and/or other physical means.
- a detectable moiety may be coupled either directly and/or indirectly (for example via a linkage, such as, without limitation, a DOTA or NHS linkage) to antibodies and antigen-binding fragments thereof of the present invention using methods well known in the art.
- a wide variety of detectable moieties may be used, with the choice depending on the sensitivity required, ease of conjugation, stability requirements and available instrumentation.
- ASPRVl protein is an aspartic peptidase
- ASPRVl protein expressed in stratified epithelia cleaves profilaggrin. It is therefore possible that the ASPRVl protein expressed in neutrophils be also capable of processing profilaggrin and other substrats even if they may not be relevant for the neutrophil activity or phenotype.
- the ASPRVl protein or fragment thereof may also be detected by peptide sequencing or other methods known to a person skilled in the art.
- ICAMl was detected on capillaries, but not on intravascular neutrophils that exhibited the rod-shaped morphology typical of crawling leukocytes 22 (Figure 2c). In contrast, ICAMl was detected on the vast majority (> 90%) of extravascular neutrophils in the meninges and parenchyma ( Figure 2d). Neutrophils were also observed in the vasculature of naive and sham-treated mice (where they were negative for ICAMl), but never in the parenchyma, as previously reported 18,19 .
- Ly6G + neutrophils Approximately 80% of all Ly6G + neutrophils from the spinal cord of EAE mice expressed ZsGreen. Curiously, Ly6G + neutrophils accounted for 78% of the ZsGreen + population, while the remaining 22% were other myeloid phagocytes: DCs, macrophages and microglia (Figure 5d).
- ASPRVl mRNA was abundant in blood neutrophils in the steady state, but not in B cells, Th cells, monocytes or unfractionated mononuclear cells (Figure 7e). Further, ASPRVl mRNA was detected in higher amounts in brain lesions from patients with severe MS compared to both normal-appearing white matter and brain lesions from patients with typical forms of MS ( Figure 7f). Therefore, our results demonstrate that ASPRV1 is a neutrophil-specific protein in the immune system and can serve as a neutrophil marker in the nervous system both in the mouse and human.
- ICAM1 facilitates cell-cell interactions such as the formation of immunological synapses 29 .
- neutrophils act, at least in part, in a contact-dependent manner in demyelination, and provide a surface marker for the study of neutrophil subpopulations.
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US201762533398P | 2017-07-17 | 2017-07-17 | |
PCT/CA2018/000140 WO2019014744A1 (en) | 2017-07-17 | 2018-07-09 | ASPRV1 AS A NEUTROPHIL SPECIFIC MARKER AND THERAPEUTIC TARGET FOR INFLAMMATORY DISEASES |
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